Central nervous system diseases related to pathological microglial phagocytosis

Abstract

Microglia are important phagocytes of the central nervous system (CNS). They play an important role in protecting the CNS by clearing necrotic tissue and apoptotic cells in many CNS diseases. However, recent studies have found that microglia can phagocytose parts of neurons excessively, such as the neuronal cell body, synapse, or myelin sheaths, before or after the onset of CNS diseases, leading to aggravated injury and impaired tissue repair. Meanwhile, reduced phagocytosis of synapses and myelin results in abnormal circuit connections and inhibition of remyelination, respectively. Previous studies focused primarily on the positive effects of microglia phagocytosis, whereas only a few studies have focused on the negative effects. In this review, we use the term "pathological microglial phagocytosis" to refer to excessive or reduced phagocytosis by microglia that leads to structural or functional abnormalities in target cells and brain tissue. The classification of pathological microglial phagocytosis, the composition, and activation of related signaling pathways, as well as the process of pathological phagocytosis in various kinds of CNS diseases, are described in this review. We hypothesize that pathological microglial phagocytosis leads to aggravation of tissue damage and negative functional outcome. For example, excessive microglial phagocytosis of synapses can be observed in Alzheimer's disease and schizophrenia, leading to significant synapse loss and memory impairment. In Parkinson's disease, ischemic stroke, and traumatic brain injury, excessive microglial phagocytosis of neuronal cell bodies causes impaired gray matter recovery and sensory dysfunction. We therefore believe that more studies should focus on the mechanism of pathological microglial phagocytosis and activation to uncover potential targets of therapeutic intervention.

Keywords: microglial phagocytosis; myelin; neuronal cell body; synapse.

FIGURE 1

Signals and molecules of pathological phagocytosis between microglia and target cell. Left panel: (A) Pathological microglial phagocytosis of synapse. (B) Pathological microglial phagocytosis of myelin sheath. (C) Pathological microglial phagocytosis of neuronal cell body. (D) Pathological microglial phagocytosis of myelin debris. The abnormal activation of "eat‐me" and "don't eat‐me" signaling pathways exists in many CNS diseases. For example, Aβ causes C1q's activation and induces excessive microglial phagocytosis of synapses (pink a). In chronic cerebral ischemia, excessive microglial phagocytosis of myelin sheaths via C3/C3aR pathway (green b). Right panel: In CNS disease, microglia recognize the "eat‐me" and "don't eat‐me" signals exposed on the surface of target cells. "Eat‐me" signals can be divided into two categories: membrane anchoring signals (eg, TIM, PtdSer) and soluble bridging molecules (eg, CR3, C1q). "Don't eat‐me" signal mediates the inhibition of microglial phagocytosis, which is mainly composed of CD47‐SIRPα

FIGURE 2

The comparison between normal phagocytosis and pathological phagocytosis. In CNS diseases, microglia phagocyte apoptotic cells, myelin debris, and damaged synapses. They play a beneficial role in neuroinflammation resolution and removal of apoptotic cells. This kind of phagocytosis can be considered normal phagocytosis. However, pathological microglial phagocytosis may occur as a result of abnormal activation of microglia. Pathological microglial phagocytosis includes reduced phagocytosis of myelin debris or synapses, and/or excessive phagocytosis of synapses, myelin sheath, and neuronal cell bodies. Reduced and excessive phagocytosis contributes to cell death, synaptic circuit dysfunction, and demyelination, ultimately resulting in exacerbation of CNS diseases